Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease

Charuhas Thakar, BEACON Trial Investigators

Research output: Contribution to journalArticlepeer-review

842 Citations (Scopus)

Abstract

BACKGROUND: Although inhibitors of the renin-angiotensin-aldosterone system can slow the progression of diabetic kidney disease, the residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)-related factor 2 activators further reduce this risk is unknown.

METHODS: We randomly assigned 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (estimated glomerular filtration rate [GFR], 15 to <30 ml per minute per 1.73 m(2) of body-surface area) to bardoxolone methyl, at a daily dose of 20 mg, or placebo. The primary composite outcome was end-stage renal disease (ESRD) or death from cardiovascular causes.

RESULTS: The sponsor and the steering committee terminated the trial on the recommendation of the independent data and safety monitoring committee; the median follow-up was 9 months. A total of 69 of 1088 patients (6%) randomly assigned to bardoxolone methyl and 69 of 1097 (6%) randomly assigned to placebo had a primary composite outcome (hazard ratio in the bardoxolone methyl group vs. the placebo group, 0.98; 95% confidence interval [CI], 0.70 to 1.37; P=0.92). In the bardoxolone methyl group, ESRD developed in 43 patients, and 27 patients died from cardiovascular causes; in the placebo group, ESRD developed in 51 patients, and 19 patients died from cardiovascular causes. A total of 96 patients in the bardoxolone methyl group were hospitalized for heart failure or died from heart failure, as compared with 55 in the placebo group (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P<0.001). Estimated GFR, blood pressure, and the urinary albumin-to-creatinine ratio increased significantly and body weight decreased significantly in the bardoxolone methyl group, as compared with the placebo group.

CONCLUSIONS: Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular causes. A higher rate of cardiovascular events with bardoxolone methyl than with placebo prompted termination of the trial. (Funded by Reata Pharmaceuticals; BEACON ClinicalTrials.gov number, NCT01351675.).

Original languageEnglish
Pages (from-to)2492-2503
Number of pages12
JournalNew England Journal of Medicine
Volume369
Issue number26
DOIs
Publication statusPublished - 26 Dec 2013
Externally publishedYes

Keywords

  • Aged
  • Cardiovascular Diseases/etiology
  • Diabetes Mellitus, Type 2/complications
  • Diabetic Nephropathies/drug therapy
  • Double-Blind Method
  • Female
  • Glomerular Filtration Rate
  • Humans
  • Intention to Treat Analysis
  • Kaplan-Meier Estimate
  • Kidney Failure, Chronic/etiology
  • Male
  • Middle Aged
  • NF-E2-Related Factor 2/metabolism
  • Oleanolic Acid/adverse effects
  • Renal Insufficiency, Chronic/drug therapy
  • Treatment Failure
  • Weight Loss/drug effects

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